Cisplatin has been successfully used to treat of a variety of cancers since the 1970s. However, patients who receive cisplatin can suffer from dose-limiting side-effects which include nephrotoxicity and ototoxicity. The ototoxic effects of cisplatin involve in part the death of sensory hair cells of the inner ear. Cisplatin causes cell death by forming DNA adducts and increasing the pool of reactive oxygen species (ROS) in cells. Two pro-apoptotic proteins known to play roles in cisplatin-induced cell death are p53 and the signal transducer and activator of transcription protein-1 (STAT-1). p53 is a major mediator of cisplatin-induced death of cancer cells (reviewed by Siddik 2003). However, recent evidence indicates that p53 is not required for cisplatin-induced death of renal proximal tubule cells in the kidney (Jiang et al. 2009). The role of p53 in cisplatin-induced death of hair cells has not been determined. Cisplatin-induced hair cell death is dependent on STAT-1 activation (Schmitt et al. 2009). Heat shock preconditioning, which results in upregulation of heat shock proteins (Hsps), inhibits cisplatin-induced hair cell death (Cunningham and Brandon 2006). One of these Hsps, Hsp32, has been shown to inhibit cisplatin-induced hair cell death in neonatal rat cochlea in vitro (Kim et al. 2006). Hsp70 is the most stress-inducible Hsp, and it can protect hair cells from aminoglycoside induced death both in vitro and in vivo (Taleb et al. 2008; Taleb et al. 2009). Both Hsp70 and Hsp32 have been shown to modulate the activation of either p53 or STAT-1. The experiments in this proposal are designed to examine the role of p53 in mediating cisplatin-induced hair cell death and to elucidate the mechanism(s) underlying the protective effects of Hsp32 and Hsp70.